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Inflammasome Inhibitors for Type 2 Diabetes

2 型糖尿病的炎症小体抑制剂

基本信息

批准号：
8253234
负责人：
Bradley J Backes
金额：
$ 18.48万
依托单位：
METAFOLD THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-18 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8253234
关键词：
Ablation Address American Animal Model Anti-Inflammatory Agents Anti-inflammatory Apoptosis Binding Biological Assay Blood Glucose Caspase-1 Cell membrane Cell physiology Cells Cellular Stress Chronic Clinical Clinical Trials Coculture Techniques Development Diabetes Mellitus Diet Disease Disease Progression Epidemic Exhibits Failure Fatty acid glycerol esters Functional disorder Generations Glucose Glyburide Goals Human Hypoglycemia Inflammation Inflammatory Insulin Insulin Resistance Interleukin-1 Interleukin-18 Interleukins International Islets of Langerhans Lead Lipids Measures Mediating Mediator of activation protein Metabolic Metabolic stress Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Oral Outcome Pancreas Pathogenesis Patients Peripheral Play Process Production Public Health Radioactive Recombinants Relative (related person)Risk Role Sepsis Signal Transduction Stimulus Structure-Activity Relationship Testing Time Treatment Protocols United States Wild Type Mouse Work anakinra cost cytokine design diabetic drug development experience extracellular feeding glucose tolerance glucose uptake glycemic control improved inhibitor/antagonist insight insulin secretagogues insulin secretion insulin sensitivity insulin signaling islet islet amyloid polypeptide macrophage novel receptor sensor tool

项目摘要

DESCRIPTION (provided by applicant): The American Diabetes Association in 2008 determined that type 2 diabetes (T2D) has reached the status of "public health crisis" costing the United States at least $174 billion a year. The pathogenesis of T2D is characterized by a combination of factors that ultimately lead to the loss of glycemic control. Approximately 60% of diabetics do not achieve their target blood sugar levels with their current treatment regimen. In addition, no existing agent reverses disease progression and all exhibit reduced efficacy over time. Chronic low-grade inflammation has emerged as a central mechanism that underlies both insulin resistance in the periphery and b-cell dysfunction and apoptosis in the pancreas. The NLRP3 inflammasome is a sensor of metabolic dysregulation that triggers the maturation and secretion of proinflammatory cytokines IL-1b and IL-18. Implicated as a critical driver of the progression from obesity to T2D, the inflammasome has emerged as an attractive target, though an incompletely understood one. Recently, glyburide has been shown to inhibit the NLRP3 inflammasome, and its insulin secretagogue activity is not responsible for these actions. In fact, glyburide's secretagogue activity is undesirable since it puts patients at risk for hyperinsulinemic hypoglycemia and contributes to b-cell dysfunction and apoptosis. We propose to optimize glyburide's inflammasome activity while designing out its secretagogue actions to produce potent and selective inhibitors. We will demonstrate that these compounds suppress IL-1b secretion in our macrophage and islet models while preserving islet function. This work will be a first step towards developing a new class of oral agents for T2D; NLRP3 inflammasome inhibitors. PUBLIC HEALTH RELEVANCE: The American Diabetes Association in 2008 determined that type 2 diabetes (T2D) has reached the status of "public health crisis" costing the United States at least $174 billion a year. The International Diabetes Federation predicts that by 2025, the cost will exceed $302.5 billion. The pathogenesis of T2D is characterized by a combination of factors that ultimately lead to loss of glycemic control. Approximately 60% of diabetics do not achieve their target blood sugar levels with their current treatment regimen. In addition, no existing agent reverses disease progression and all exhibit reduced efficacy over time. We seek to create and develop oral therapies for T2D that address the chronic low-grade inflammation that drives disease progression. Our efforts represent significant steps towards the development of a novel, oral treatment to improve glycemic control in type 2 diabetics with the unique potential to modify disease progression.

描述（由申请人提供）：美国糖尿病协会在2008年确定2型糖尿病（T2 D）已经达到“公共卫生危机”的状态，每年花费美国至少1740亿美元。T2 D的发病机制的特征在于最终导致血糖控制丧失的因素的组合。大约60%的糖尿病患者在目前的治疗方案下无法达到目标血糖水平。此外，没有现有的药物逆转疾病进展，并且随着时间的推移，所有药物都表现出降低的疗效。慢性低度炎症已经成为一种中心机制，它是外周胰岛素抵抗和胰腺b细胞功能障碍和细胞凋亡的基础。NLRP 3炎性小体是代谢失调的传感器，其触发促炎细胞因子IL-1b和IL-18的成熟和分泌。作为从肥胖到T2 D进展的关键驱动因素，炎性小体已成为一个有吸引力的目标，尽管尚未完全理解。最近，格列本脲已显示出抑制NLRP 3炎性体，其胰岛素促分泌活性不是这些作用的原因。事实上，格列本脲的促分泌活性是不受欢迎的，因为它使患者处于高胰岛素血症性低血糖的风险中，并导致b细胞功能障碍和细胞凋亡。我们建议优化格列本脲的炎性体活性，同时设计出其促分泌作用，以产生有效的和选择性的抑制剂。我们将证明这些化合物抑制巨噬细胞和胰岛模型中的IL-1b分泌，同时保留胰岛功能。这项工作将是开发新型T2 D口服药物的第一步; NLRP 3炎性体抑制剂。公共卫生关系：美国糖尿病协会在2008年确定2型糖尿病（T2 D）已经达到“公共卫生危机”的状态，每年花费美国至少1740亿美元。国际糖尿病联合会预测，到2025年，费用将超过3025亿美元。T2 D的发病机制的特征在于最终导致血糖控制丧失的因素的组合。大约60%的糖尿病患者在目前的治疗方案下无法达到目标血糖水平。此外，没有现有的药物逆转疾病进展，并且随着时间的推移，所有药物都表现出降低的疗效。我们寻求创建和开发T2 D的口服疗法，以解决驱动疾病进展的慢性低度炎症。我们的努力代表了开发一种新型口服治疗方法的重要步骤，该方法可改善2型糖尿病患者的血糖控制，具有独特的改善疾病进展的潜力。